PROJECT SUMMARY Cancer is the second leading cause of deaths in the United States and it has become a serious economic burden to society. Among the most successful treatments, natural product inspired chemotherapies such as Paclitaxel, Navelbine and Eribulin have significantly extended the life span of millions of cancer patients. It has been reported that more than 75% of the new chemical entities submitted to the Food and Drug Administration as anticancer agents between 1940 and 2010 have natural product origins. We propose to develop a novel oxidative dearomatization methodology to access the core structures of biologically active natural products and investigate its application to the total synthesis of daphmanidin A, an alkaloid showing significant cytotoxicity against murine lymphoma cells. Because some subtypes of lymphoma do not form solid tumors, their treatments commonly involve intense radiotherapy and chemotherapy. To improve the prognosis of patients who show low tolerance to current high dose regimens, new therapeutic agents with better efficacy are urgently needed. Given the cytotoxicity profiles of Daphniphyllum alkaloids, it is important to study the biology of daphmanidin A and explore its potential to become a therapeutic agent. Our preliminary data have shown that an enantioselective Michael addition / oxidative dearomatization cascade can be achieved by a one-pot operation, and the desired products are obtained with excellent stereoselectivity and yields, highlighting the remarkable efficiency of our strategy for the synthesis of these natural products. When para substituted phenols are subjected to the dearomatization, the core structures of Cephalotaxus norditerpenes are conveniently produced. When ortho substituted phenols are intercepted during the dearomatization, the spiro intermediates can serve as dienes in the subsequent [4+2] cycloaddition, resulting in the daphmanidin A type alkaloid skeletons. In the proposed research we will 1) identify the suitable single electron transfer reagent and base to enable the dearomatization for sensitive substrates under homogenous conditions; 2) study the regioselectivity for asymmetrically substituted aromatics; 3) examine the conditions to intercept spiro diene in the dearomatization; 4) elucidate the stereochemistry determining elements that control the chirality of the quaternary carbon center, and 5) apply the novel methodology to the synthesis of daphmanidin A and its pharmaceutically relevant analogues.